Method The Center for Epidemiologic Study depression scale
(CES—D) and the Mini-Mental State Examination (MMSE) were used to
evaluate depressive symptomatology and cognitive functioning, respectively. A
sample of 1003 persons aged 59-71 years and with a MMSE score of 26 or over
was selected. Cognitive decline was defined as a drop of at least 3 points on
the MMSE at 4-year follow-up.

Results Baseline high levels of depressive symptoms predicted a
higher risk of cognitive decline at 4-year follow-up. The MMSE score of
participants with depression was more likely to fall below 26 at 2-year
follow-up and to remain below at 4-year follow-up than the MMSE score of those
without depressive symptoms. Persistent but not episodic depressive episodes
were associated with cognitive decline.

Conclusions High levels of depressive symptoms, when persistent, are
associated with cognitive decline in a sample of elderly people.

Many studies have shown an association between depressive symptoms and
dementia or cognitive decline (Jorm,
2000) but the nature of this relationship remains equivocal.
Depressive symptoms have been found to precede cognitive decline
(Yaffe et al, 1999)
or to follow the onset of dementia (Chen
et al, 1999). Some studies did not report any significant
association (Dufouil et al,
1996; Palsson et al,
1999). Bassuk et al
(1998) found that depression
predicted cognitive decline over 3-year and 6-year follow-up periods for
people with medium, but not high, cognitive scores at baseline. Geerlings
et al (2000) found
that depression was associated with an increased risk of Alzheimer's disease
and cognitive decline only in people with higher levels of education. The
objectives of our study were:

to test whether depressive symptoms predict cognitive decline in an elderly
population with normal cognition;

to examine whether people reporting episodic or persistent depressive
episodes show a similar or different association with cognitive decline.

METHOD

Sample and study design

The Étude sur le Vieillissement Artériel (EVA) is a
longitudinal study of cognitive and vascular ageing. The EVA study population
consisted of 1389 persons born between 1922 and 1932, who were selected from
the electoral rolls of the city of Nantes in western France, and were invited
by mail to participate in the study. The survey design was approved by the
ethics committee of the University Hospital of Bicêtre, and written
consent was required for each participant. Baseline data were collected
between June 1991 and June 1993.

Interviews and examinations were conducted at the study centre. Data on
demographic background, occupation, medical history, drug use and personal
habits were obtained using a standardised questionnaire during a face-to-face
interview. Mean weekly alcohol intake was estimated from a detailed
description of alcoholic beverage consumption during a typical week.
Participants were asked whether they had suffered from any of six specified
common diseases (myocardial infarction, angina, stroke, hypercholesterolaemia,
hypertension, diabetes) or had any other chronic medical condition. All drugs
used during the month preceding the examination were noted, and were
subsequently coded according to the classification proposed by the French
national prescription handbook, the Guide National de Prescription des
Médicaments
(1991). Psychotropic drugs
included anxiolytic, hypnotic, sedative, neuroleptic, antidepressant and
normothymic agents.

The group was invited to participate in two follow-up examinations, which
were conducted 2 years and 4 years after the baseline evaluation.

Population

Among the initial sample of 1389 persons, 200 (14.4%) had a baseline score
on the Mini-Mental State Examination (MMSE) below 26 and were excluded from
the analysis. Of the 1189 persons considered eligible for the study, 18 died
before the 4-year follow-up assessment, 137 were not followed up at 2 years or
4 years, and 31 had not completed the Center for Epidemiologic Studies
depression scale (CES—D) rating at baseline. So, 84% of eligible
participants were analysed (n=1003). A further 31 participants had no
CES—D assessment at 2-year or 4-year follow-up.

Cognitive function testing

A trained psychologist administered a battery of tests assessing different
areas of cognitive and psychomotor functioning. Tests were chosen with special
regard for their sensitivity to ageing. For the current analysis we considered
a measure of global cognitive abilities, the MMSE
(Folstein et al,
1975), which yields scores ranging from 0 to 30. The MMSE was
administered to participants at baseline and at 2-year and 4-year
follow-up.

Assessment of depressive symptoms

Depressive symptoms were measured using the CES—D
(Radloff, 1977). It consists
of 20 self-report items concerning symptoms and feelings experienced during
the preceding week. Each item is scored from 0 to 3 according to the frequency
of the symptom. Evaluation of the CES—D in a French population
(Fuhrer & Rouillon, 1989)
showed that men and women scoring more than 16 or 22, respectively, should be
considered at high risk of clinical depression. Using this cut-off point the
authors obtained a sensitivity and specificity which were, respectively, 0.76
and 0.71 in detecting a major depressive episode according to DSM—III
criteria (American Psychiatric Association,
1980). In our study the internal consistency of the CES—D
was good (standardised Cronbach's α=0.88). Work with the CES—D in
community samples has consistently identified four factors that underlie the
measure: depressed affect, positive affect, somatic complaints and
interpersonal relationships.

The CES—D was sent to the participants by mail approximately 3 weeks
before the examination and completed questionnaires were brought back at the
time of the examination. The instrument was administered to the participants
at the baseline assessment and at 2-year and 4-year follow-up.

Data analysis

We excluded from the data analysis people with a baseline MMSE score lower
than 26 for two reasons: to exclude those with subthreshold levels of
dementia, and to include only those at risk of cognitive decline.

The differences in MMSE scores between baseline and 4-year follow-up
examinations were analysed as quantitative variables, and also as binary
variables. For the latter analyses, cognitive decline was defined as a
decrease of 3 points or more in the MMSE scores. We defined ‘low
cognitive functioning at follow-up’ as MMSE scores of 25 or less at
2-year and 4-year follow-up. Participants were defined as having high baseline
levels of depressive symptoms when their baseline CES—D score was above
the gender-specific cut-off point. In order to evaluate whether the risk of
cognitive decline is higher when the participant reports several depressive
episodes at follow-up evaluation, we defined three study groups. Participants
reporting high levels of depressive symptoms at one or at more than one
evaluation were assigned to an ‘episodic’ or a
‘
persistent’ depressive group, respectively, and were compared
with participants who did not have high depressive symptom scores at any of
the three assessments.

We tested whether a high depressive symptom score was associated with
cognitive decline using multivariate analyses (covariance analysis and
logistic regression models). All multivariate analyses were adjusted for
gender, age, education (years of schooling), alcohol (mean weekly alcohol
intake evaluated in millilitres of pure alcohol) and tobacco use (current
smokers, former smokers, or never smokers), psychotropic drug use and the
presence of chronic medical diseases, because these variables are known to be
significantly associated with cognitive performance and psychopathological
characteristics.

In order to examine whether the observed relationship between CES—D
score and cognitive decline was due to depressed mood rather than to the
cumulative number of symptoms, we evaluated whether the CES—D sub-score
‘
depressive affect’ was predictive of cognitive decline, using
linear and logistic regression models. We calculated the ‘depressive
affect’ subscore, by summing the scores of items measuring the cognitive
symptoms of depression (‘bothered’, ‘blues’,
‘
depressed’, ‘fearful’, ‘lonely’,
‘
cried’ and ‘sad’)
(Radloff & Teri, 1986).
The sub-score ranged from 0 to 21.

Statistical testing was done at the conventional two-tailed α-level
of 0.05. Data were analysed using the SAS package, Version 6
(SAS Institute, 1989).

RESULTS

Population characteristics

The population characteristics are shown in
Table 1. Participants with high
levels of depressive symptoms more often used tobacco and psychotropic
drugs.

Comparison between participants according to follow-up

A slightly higher percentage of participants who were not followed up had a
high depressive symptom score at baseline; they also had lower MMSE scores
than those followed up. Participants not followed up had fewer years of
schooling and used more psychotropic drugs. No difference was observed for
gender, age or alcohol use.

Depressive symptoms at baseline and the risk of cognitive
decline

Participants with high levels of depressive symptoms showed a greater
decrease in MMSE score between the baseline and 4-year follow-up assessments
(Table 2). High levels of
depressive symptoms were also associated with a higher risk of a 3-point
decrease in MMSE score and with a higher risk of low cognitive functioning at
follow-up.

Depressive symptoms at baseline and risk of cognitive decline at 4-year
follow-up

Persistent depressive symptoms and cognitive decline

Persistent — but not episodic — depressive symptoms were
associated with greater cognitive decline and with low cognitive functioning
at follow-up (Table 3). In
order to test whether persistent but not episodic depressive symptoms
predicted cognitive decline in those with depressive symptoms at baseline, we
compared participants depressed at baseline but not at 2-year and 4-year
follow-up (‘episodic’, n=39) and participants depressed
at baseline and at 2-year and/or 4-year follow-up (‘persistent’,
n=77) with participants not depressed at baseline. The
‘
persistent’ group had twice the risk of cognitive decline (odds
ratio 2.0, 95% CI 1.1-3.5) of participants who were not depressed; episodic
depressive symptoms were not associated with cognitive decline (OR 0.8, 95% CI
0.3-2.2).

The finding that depressive symptoms predict cognitive decline might be due
to depressive symptoms being the consequence of a slight initial cognitive
decline. In order to test this possibility, we considered the group of
participants without cognitive decline between baseline and 2-year follow-up
(Table 4). A high level of
depressive symptoms at 2-year follow-up was associated with a greater decrease
in MMSE score between the 2-year and 4-year follow-up assessments in this
group.

Difference in Mini-Mental State Examination (MMSE) scores according to
level of depressive symptoms in participants without previous cognitive
decline

Depressive affect

Linear and logistic regression models adjusted for baseline cognitive
scores and covariables were used to examine the association between the
sub-score ‘depressive affect’ and cognitive decline. In a linear
regression model, depressive affect was associated with a greater decrease in
MMSE score between baseline and 4-year follow-up (b=-0.06, s.e.=0.02,
P=0.0003). Logistic regressions showed that depressive affect was
also associated with a higher risk of low cognitive functioning at follow-up
(OR 1.07, 95% CI 1.01-1.13) and a higher risk of a 3-point decrease in MMSE
score (OR 1.06, 95% CI 1.00-1.12).

DISCUSSION

In this study initially high levels of depressive symptoms predicted
cognitive decline in an elderly population of 1003 persons with good cognitive
functioning at recruitment. People with initially high depressive symptom
levels were more at risk of having persistent low cognitive functioning at
follow-up. These associations concerned those with persistent but not episodic
depressive symptoms. These results are in agreement with longitudinal studies
showing that depressive symptoms are predictive of cognitive decline
(Bassuk et al, 1998;
Chen et al, 1999;
Yaffe et al, 1999;
Geerlings et al,
2000).

Mechanisms of association

Different mechanisms may explain why depressive symptoms predict cognitive
decline. Depression may be a psychological reaction to perceived cognitive
loss. Schmand et al
(1997) found that depressive
symptoms at baseline did not predict future dementia when memory complaints
were accounted for. In our study depressive symptoms preceded cognitive
decline, in the absence of previous loss of cognitive performance; it is
therefore unlikely that in our group depression is only a psychological
reaction to perceived cognitive loss. On the other hand, it is possible that
the MMSE does not permit the evaluation of finer cognitive losses. Cognitive
deficits usually associated with depression may be responsible for an earlier
onset of cognitive decline or dementia. However, in our study depressive
symptoms also predicted cognitive decline in participants with the highest
MMSE scores, so it is not likely that this phenomenon can explain all the
data.

Somatic symptoms such as fatigue or concentration disorders may be early
symptoms of dementia; they are also symptoms of depressive disorders and are
included as items of depression rating scales. A high depression score may
thus reflect early symptoms of dementia. In our study, the observation that
the affective dimension of CES—D was predictive of cognitive decline
shows that the observed association between depressive score and subsequent
cognitive decline was not only due to the somatic component of depression.

In our study group of people with initial depressive symptoms, persistent
(but not episodic) depression was associated with a higher risk of cognitive
decline. This result is in agreement with the observation that people with
depressive symptoms often suffer from cognitive impairment, which may be
severe (pseudo-dementia) but is generally transitory and resolves on treatment
of the depression (Stoudemire et
al, 1993). The fact that initially high levels of depressive
symptoms predict subsequent persistent low cognitive functioning together with
the observation that persistent but not episodic depressive episodes are
associated with cognitive decline suggest that a chronic mechanism is
responsible for the observed association. Depressive symptoms may be a
prodrome of cognitive decline — the early manifestation of a
neurodegenerative process, causing depression and dementia. Depressive
symptoms and cognitive decline are linked to modifications in activity of
similar cerebral areas (Baker et
al, 1997). Some studies have found that both are associated
with the presence of signal hyperintensities on magnetic resonance brain scans
(O'Brien et al,
1996). The loss of noradrenergic neurons associated with dementia
might also explain depression as a prodrome of dementia
(Förstl et al,
1992). Alternatively, depression might represent a causal factor
in cognitive decline. Some studies indicate that early-onset depression
(Palsson et al, 1999)
or depression that has a history of 10 years or more
(Speck et al, 1995)
are stronger risk factors for dementia. Some authors have proposed that
chronic depression causes cognitive decline by the release of
adrenocorticotrophic hormone and the consequent secretion of glucocorticoids
(O'Brien, 1997). Prolonged
secretion of glucocorticoids may have harmful effects and lead to hippocampal
atrophy (Sapolsky, 1996).

Practical and clinical implications

Although it is not possible to define causal mechanisms in an
epidemiological study, the fact that depression predicts cognitive decline in
elderly people has practical and clinical implications. The detection of
depressive symptoms in these people is important because early treatment of
depression may improve prognosis. In addition, depressive symptoms, especially
when they are persistent, may be the first sign of the decrease in cognitive
functioning, carrying not only a higher risk of dementia, but also a higher
mortality (Gussekloo et al,
1997; Rozzini et al,
1998). People with cognitive decline may benefit from drugs that
might slow the progression of the disease. Nevertheless, diagnosis of
depression is more difficult in elderly people, in whom symptoms such as
fatigue, loss of libido and sleep disturbances occur more frequently even in
the absence of depression. A possible consequence is that chronic depression
in this age group may be underdiagnosed, because somatic symptoms are
attributed to physical rather than psychiatric causes
(Hasin & Link, 1988). In
our study only 4% of the group with high levels of depressive symptoms were
receiving specific (anti-depressant) treatment. A high proportion of people
with chronic depression use benzodiazepines
(Bonner & Howard, 1995),
which have been associated in the elderly with a higher risk of cognitive
impairment (Gorenstein et al,
1995).

Limitations of the study

In our study no history of depressive symptoms was obtained and no
diagnosis of depressive disorder was made. It cannot therefore be deduced
whether early or late depression is responsible for cognitive decline and
which clinical form of depression is associated with cognitive impairment.
Moreover, study participants who were not followed up had higher levels of
depressive symptoms and lower MMSE scores at baseline than those who were
followed up. The association between depressive symptoms and cognitive decline
may be underestimated. However, few patients were lost to follow-up (13%) and
so major bias is unlikely.

In conclusion, our finding that depressive symptoms predict cognitive
decline may have important clinical implications. Depression may be a
harbinger of initial cognitive decline.

Clinical Implications and Limitations

CLINICAL IMPLICATIONS

Initially, people with depression who have good cognitive functioning are
more likely to show a subsequent persistent reduction in cognitive functioning
than people who are not depressed.

Cognitive decline is more likely in those reporting persistent rather than
episodic depression.

LIMITATIONS

Without a history of depressive symptoms or a diagnosis of depressive
disorder for the patients in this study it is not possible to establish
whether early or late depression is responsible for cognitive decline or which
clinical form of depression is associated with cognitive decline.

Participants who were not followed up (13%) had higher levels of depressive
symptoms and lower Mini-Mental State Examination (MMSE) scores at baseline
than those who were followed up; the association between depressive symptoms
and cognitive decline may therefore be underestimated.

Although our data suggest that depressive symptoms predict cognitive
decline in study participants with previously stable good performances, it is
possible that the MMSE was inadequate to detect more subtle cognitive
decline.